PT  - JOURNAL ARTICLE
AU  - Wichmann, Christian W.
AU  - Morgan, Katherine A.
AU  - Cao, Zhipeng
AU  - Osellame, Laura D.
AU  - Guo, Nancy
AU  - Gan, Hui
AU  - Reilly, Edward
AU  - Burvenich, Ingrid J.G.
AU  - O’Keefe, Graeme J.
AU  - Donnelly, Paul S.
AU  - Scott, Andrew M.
TI  - Radiolabeling and Preclinical Evaluation of Therapeutic Efficacy of <sup>225</sup>Ac-ch806 in Glioblastoma and Colorectal Cancer Xenograft Models
AID  - 10.2967/jnumed.123.266894
DP  - 2024 Sep 01
TA  - Journal of Nuclear Medicine
PG  - 1456--1462
VI  - 65
IP  - 9
4099  - http://jnm.snmjournals.org/content/65/9/1456.short
4100  - http://jnm.snmjournals.org/content/65/9/1456.full
SO  - J Nucl Med2024 Sep 01; 65
AB  - The epidermal growth factor receptor (EGFR) protein is highly expressed in a range of malignancies. Although therapeutic interventions directed toward EGFR have yielded therapeutic responses in cancer patients, side effects are common because of normal-tissue expression of wild-type EGFR. We developed a novel tumor-specific anti-EGFR chimeric antibody ch806 labeled with 225Ac and evaluated its in vitro properties and therapeutic efficacy in murine models of glioblastoma and colorectal cancer. Methods: 225Ac-ch806 was prepared using different chelators, yielding [225Ac]Ac-macropa-tzPEG3Sq-ch806 and [225Ac]Ac-DOTA-dhPzPEG4-ch806. Radiochemical yield, purity, apparent specific activity, and serum stability of 225Ac-ch806 were quantified. In vitro cell killing effect was examined. The biodistribution and therapeutic efficacy of 225Ac-ch806 were investigated in mice with U87MG.de2-7 and DiFi tumors. Pharmacodynamic analysis of tumors after therapy was performed, including DNA double-strand break immunofluorescence of γH2AX, as well as immunohistochemistry for proliferation, cell cycle arrest, and apoptosis. Results: [225Ac]Ac-macropa-tzPEG3Sq-ch806 surpassed [225Ac]Ac-DOTA-dhPzPEG4-ch806 in radiochemical yield, purity, apparent specific activity, and serum stability. [225Ac]Ac-macropa-tzPEG3Sq-ch806 was therefore used for both in vitro and in vivo studies. It displayed a significant, specific, and dose-dependent in vitro cell-killing effect in U87MG.de2-7 cells. 225Ac-ch806 also displayed high tumor uptake and minimal uptake in normal tissues. 225Ac-ch806 significantly inhibited tumor growth and prolonged survival in both U87MG.de2-7 and DiFi models. Enhanced γH2AX staining was observed in 225Ac-ch806–treated tumors compared with controls. Reduced Ki-67 expression was evident in all 225Ac-ch806–treated tumors. Increased expression of p21 and cleaved caspase 3 was shown in U87MG.de2-7 and DiFi tumors treated with 225Ac-ch806. Conclusion: In glioblastoma and colorectal tumor models, 225Ac-ch806 significantly inhibited tumor growth via induction of double-strand breaks, thereby constraining cancer cell proliferation while inducing cell cycle arrest and apoptosis. These findings underscore the potential clinical applicability of 225Ac-ch806 as a potential therapy for EGFR-expressing solid tumors.